Throughout this application various publications are referenced by numbers. The full citations are listed at the end of the specification immediately preceeding the claims.
The proteinase-antiproteinase concept of emphysema has served to focus research on the role of elastases, with the hope that inhibiting the activity of these enzymes will prevent lung injury (1-4). Such a treatment strategy assumes, however, that emphysema is caused by a specific type of biochemical derangement, as in the case of alpha-1-antiproteinase deficiency (5). If the disease represents a more general response of the lung to a variety of insults (with elastases playing a variable role), then enzyme inhibition may have only limited efficacy.
In attempting to address the issue of whether emphysema is a specific or multifactorial disease process, a series of experiments were previously performed by this laboratory involving both the induction and modification of experimental emphysema with agents other than elastases. It was found that elastase-induced emphysema is greatly enhanced by exposing the lungs to a normally nontoxic concentration of oxygen (60 percent) (6). Similarly, it was possible to produce air-space enlargement with a nonelastolytic enzyme, hyaluronidase, by the addition of 60 percent oxygen (7). The experiments using hyaluronidase and 60 percent oxygen showed that loss of lung elastin occurred only when both agents were given concomitantly, suggesting the possibility that hyaluronidase may facilitate the breakdown of elastic fibers by making them more accessible to injury.
This hypothesis was further tested in the current studies. To test this invention, hamsters were given intratracheal instillments of hyaluronidase, followed by elastase, and then examined for air-space enlargement. The findings indicate that pretreatment with hyaluronidase enhances elastase-induced emphysema. Furthermore, it was found that intratracheally administered hyaluronic acid had the opposite effect (despite its inability to directly inhibiting elastase). These results provide additional evidence that air-space enlargement is a complex phenomenon and that new approaches to the treatment of emphysema may be required.